MET Resistance Alterations
What are resistance alterations?
When cancer is treated with targeted therapy, it can eventually find ways around the drug. This is called acquired resistance. The tumor evolves under treatment pressure, developing new alterations that allow it to survive despite the therapy. Understanding which resistance mechanism is driving progression matters because different mechanisms may respond to different treatments.
MET alterations are involved in resistance in two distinct ways: MET can be the primary driver that acquires resistance to MET-targeted therapy, and MET can emerge as a resistance mechanism in cancers originally driven by a different alteration.
MET as a resistance mechanism to EGFR inhibitors
MET amplification is one of the most common acquired resistance mechanisms in EGFR-mutant non-small cell lung cancer treated with osimertinib (Tagrisso). It is estimated to occur in 7 to 18% of patients who progress on osimertinib, making it a clinically significant and increasingly recognized pattern.
When MET amplification drives resistance to an EGFR inhibitor, the cancer has activated the MET pathway as an alternative survival route. Combining an EGFR inhibitor with a MET inhibitor (such as capmatinib or tepotinib) is an active area of investigation, with several clinical trials underway.
If your EGFR-targeted therapy stopped working, ask about MET testing.
Repeat molecular testing at progression — both tissue and liquid biopsy — can identify MET amplification as a resistance driver. This finding may open doors to clinical trials or combination treatment strategies that would not otherwise be considered.
Resistance to MET-targeted therapy
Cancers with primary MET alterations treated with MET inhibitors like capmatinib or tepotinib can also develop resistance over time. Known resistance mechanisms include secondary MET mutations (such as D1228N, D1228H, and Y1230 variants) that alter the MET kinase domain and reduce drug binding, as well as bypass pathway activation through other oncogenic drivers.
What this means for you
If your cancer has progressed on any targeted therapy, repeat comprehensive molecular testing is strongly recommended. This includes both DNA and RNA-based sequencing where available. Liquid biopsy can provide a rapid first look; tissue biopsy may be needed to confirm resistance mechanisms fully.
MET Crusaders can help you connect with oncologists experienced in MET resistance and identify clinical trials relevant to your specific resistance profile. Contact us at info@metcrusaders.org.